Atomoxetine

Article Author:
Douglas Fedder
Article Author:
Himanshu Patel
Article Editor:
Abdolreza Saadabadi
Updated:
6/12/2020 7:28:09 PM
PubMed Link:
Atomoxetine

Indications

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children over the age of 6. Although atomoxetine is only FDA approved for the treatment of ADHD, it is sometimes used off-label for the treatment of adult patients with treatment-resistant depression. It is available as a generic.[1][2][3]

Mechanism of Action

Atomoxetine is a selective, presynaptic, norepinephrine reuptake inhibitor, also known as a NET inhibitor. Atomoxetine is the R(-) isomer of the racemic mixture of R and S isomers. The R isomer is an approximately nine times more potent inhibitor of norepinephrine reuptake than the S isomer. Atomoxetine achieves its therapeutic effects by increasing the levels of intra-synaptic norepinephrine in the central nervous system (CNS). Atomoxetine also increases extracellular levels of dopamine in the prefrontal cortex, believed to result from NET inhibition. Recent studies on rhesus monkeys using positron emission tomography have shown that atomoxetine also occupies serotonin transporters, but more research in this area is still needed.[4][5][6][7][8]

Specific studies regarding the intestinal permeability of atomoxetine are not available; however, two studies on the bioavailability of atomoxetine determined that in extensive metabolizers, the bioavailability of atomoxetine was 63%, and in poor metabolizers, the bioavailability was 94%. The differences in bioavailability were attributed to differences in first-pass metabolism in the liver rather than differences in intestinal absorption. Another study comparing the bioavailability of atomoxetine capsules versus solution found no differences in bioavailability between the two. Another study looking at the absorption of atomoxetine found no differences across a range of gastrointestinal pH levels, indicating that concurrent use of antacids and proton pump inhibitors should not be cause for concern when administering atomoxetine.

The duration of action for atomoxetine can be up to 24 hours, depending on its rate of metabolism.

The volume of distribution of atomoxetine is approximately 0.85 L/kg, which is only slightly higher than the volume of total body water. For this reason, the belief is that atomoxetine is distributed into total body water. Peak concentrations of atomoxetine in plasma occurred 1 to 2 hours after administration, but may be delayed by a high-fat meal. Researchers studied the CNS pharmacokinetics of atomoxetine in rats. The penetration of the blood-brain barrier (BBB) is crucial in the pharmacokinetics of atomoxetine, as the CNS is the site of action for atomoxetine. The ratio of brain extracellular fluid (ECF) to plasma concentrations of atomoxetine was determined to be 0.7 +/- 0.4, suggesting that movement across the BBB is primarily via diffusion rather than an active transport mechanism.

In vitro studies have shown that atomoxetine is approximately 98.7% protein-bound, with albumin making up 97.5% of this binding. The high protein binding of atomoxetine raises concerns about possible drug-to-drug interactions due to displacement from plasma proteins. In vitro studies have demonstrated that plasma protein binding in humans was only reduced by toxic concentrations of acetylsalicylic acid (aspirin), indicating minimal clinical risk for drug-to-drug interactions.

Metabolism of atomoxetine primarily occurs in the liver via the action of CYP2D6, an enzyme that is involved in the metabolism of around 25% of all marketed drugs. CYP2D6 genes are highly polymorphic;

Approximately 7% of White race people and less than 1% of the Asian population are poor metabolizers of CYP2D6, and this polymorphism results in altered atomoxetine pharmacokinetics. Oral bioavailability becomes reduced (63% in extensive metabolizers of CYP2D6 and 94% in poor metabolizers), and the estimated half-life is extended (5.2 hours in extensive metabolizers and 21.6 hours in poor metabolizers).

The primary metabolite of atomoxetine, 4-hydroxy atomoxetine, has biological activity equally potent to that of atomoxetine. The half-life of atomoxetine is approximately 5 hours and may reach up to 24 hours in poor metabolizers. The active metabolite of atomoxetine has a half-life of 6 to 8 hours and may reach up to 40 hours in poor metabolizers. Atomoxetine is excreted primarily through the urine (83%) and feces (17%).

Administration

Atomoxetine is available in 10-mg, 18-mg, 25-mg, 40-mg, 60-mg, 80-mg, and 100-mg capsules as a hydrochloride salt. Patients can take atomoxetine with or without food as a once-daily dose in the morning, or as two evenly divided doses in the morning and afternoon. Capsules should not be opened and should be taken whole. Initial dosing for adults is 40 mg per day and can be increased after a minimum of 3 days to achieve therapeutic effects. A maximum daily dose is 100 mg per day. Initial dosing for children older than six years and less than 70 kg is 0.5 mg/kg per day. The maximum daily dose of 1.4 mg/kg per day or 100 mg, whichever is less.

Atomoxetine was the first non-stimulant medication to receive FDA approval for the treatment of ADHD. Previous medications approved to treat ADHD such as methylphenidate and other amphetamines are all classified as CNS stimulants, they may carry a higher risk of abuse and addiction than atomoxetine. Clinical studies of atomoxetine have shown a lack of abuse potential, consistent with preclinical predictions. While atomoxetine has demonstrated to be effective in treating ADHD, many studies have shown stimulant medications have greater efficacy. Also, stimulant medications typically have an almost immediate clinical effect; whereas, atomoxetine may take several weeks for full noticeable therapeutic action.

Caution is necessary when administering atomoxetine to individuals with hepatic impairment. Mild hepatic impairment requires no dosing adjustments. Doses should decrease to 50% of normal in individuals with moderate hepatic impairment (Child-Pugh class B), and 25% of normal in individuals with severe hepatic impairment (Child-Pugh class C).

Patients may stop taking atomoxetine without tapering.[9][10]

Adverse Effects

Atomoxetine has a United States (US) boxed warning for suicidal ideation in children and adolescents. An analysis of multiple short-term trials revealed an increase in suicidal ideation in children and adolescents treated with atomoxetine (0.4%) compared to those treated with a placebo (0%). Children and adolescents who start on atomoxetine require close monitoring for suicidal ideation and unusual changes in behavior. Clinicians should always perform a risk-benefit analysis before starting anyone on atomoxetine.

Other Adverse Effects

Greater than 10%

Headache (19%), insomnia (1% to 19%), drowsiness (8% to 11%), hyperhidrosis (4% to 15%), xerostomia (17% to 35%), nausea (7% to 26%), decreased appetite (15% to 23%), abdominal pain (7% to 18%), vomiting (4% to 11%), constipation (1% to 11%), erectile dysfunction (8% to 21%)

One percent to 10%

Increased diastolic blood pressure (5% to 9%; greater than or equal to 15 mm Hg), systolic hypertension (4% to 5%), palpitations (3%), cold extremities (1% to 3%), syncope (less than or equal to 3%), flushing (greater than or equal to 2%), orthostatic hypotension (less than or equal to 2%), tachycardia (less than or equal to 2%), prolonged QT interval on ECG, fatigue (6% to 10%), dizziness (5% to 8%), depression (4% to 7%), disturbed sleep (3% to 7%), irritability (5% to 6%), jitteriness (2% to 5%), abnormal dreams (4%), chills (3%), paresthesia (adults 3%; postmarketing observation in children), anxiety (greater than or equal to 2%), hostility (children and adolescents 2%), emotional lability (1% to 2%), agitation, restlessness, sensation of cold, excoriation (2% to 4%), skin rash (2%), pruritus, uticaria, weight loss (2% to 7%), decreased libido (3%), hot flash (3%), increased thirst (2%), menstrual disease, dyspepsia (4%), anorexia (3%), dysgeusia, flatulence ejaculatory disorder (2% to 6%), urinary retention (1% to 6%), dysmenorrhea (3%), dysuria (2%), orgasm abnormal, pollakiuria, prostatitis, testicular pain, urinary frequency, tremor (1% to 5%), muscle spasm, weakness, blurred vision (1% to 4%), conjunctivitis (1% to 3%), mydriasis, and pharyngolaryngeal pain.

Contraindications

Contraindications to atomoxetine include allergy to atomoxetine, use of an MAOI within the last 14 days, narrow-angle glaucoma, history of pheochromocytoma, and cardiac disorders which cannot tolerate increases in blood pressure or heart rate.

Because of the potential for interaction with CYP2D6 inhibitor(paroxetine and fluoxetine, quinidine) dosages of atomoxetine needs to be adjusted to prevent side effects from a higher concentration of atomoxetine.

Women of childbearing age prescribed atomoxetine should use appropriate contraceptive measures as the adverse effects of atomoxetine use during pregnancy have not been investigated thoroughly. Women who are breastfeeding should exercise caution when taking atomoxetine as it is unknown if atomoxetine is excreted in breast milk.

Monitoring

Children prescribed atomoxetine should have their growth monitored. All patients started on atomoxetine should have their vital signs monitored. Also, all patients require monitoring for attention, hyperactivity, anxiety, aggression/hostility, and suicidal ideation.

Toxicity

Exercise caution when prescribing atomoxetine with other medications metabolized via CYP2D6 as plasma concentrations can be significantly affected, leading to toxicity. Evidence regarding the toxicity of atomoxetine is limited, with much of the data coming from case studies of overdoses. Tachycardia, nausea, vomiting, and hypertension were among the most common symptoms of toxicity. Activated charcoal therapy and support of vital signs appear to be sufficient care during acute toxicity.

The concomitant administration of atomoxetine and MAOIs is contraindicated because the combination may increase the risk of serious and potentially fatal adverse events, including hyperthermia, rigidity, myoclonus, autonomic instability, extreme agitation, and mental status changes, leading to delirium and coma. A two-week washout period should occur between the discontinuation and initiation of either of these agents.

Enhancing Healthcare Team Outcomes

Atomoxetine is sometimes used to treat ADHD. However, all healthcare workers who look after these patients need to monitor the children closely regarding their growth. Also, recording vital signs must take place at each clinic visit. Finally, the medication can significantly affect behavior, and thus the child needs to be monitored for anxiety, aggression/hostility, and suicidal ideation. If adverse effects appear, discontinue the drug, and the child referred back to the mental health professional. The outcomes for children treated with atomoxetine are fair; some children do respond positively, but adverse effects often reduce compliance. [Level 5]


References

[1] Patra S,Nebhinani N,Viswanathan A,Kirubakaran R, Atomoxetine for attention deficit hyperactivity disorder in children and adolescents with autism: A systematic review and meta-analysis. Autism research : official journal of the International Society for Autism Research. 2019 Jan 17;     [PubMed PMID: 30653855]
[2] Kasparbauer AM,Petrovsky N,Schmidt PM,Trautner P,Weber B,Sträter B,Ettinger U, Effects of nicotine and atomoxetine on brain function during response inhibition. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2018 Dec 12;     [PubMed PMID: 30552041]
[3] Jensen CM,Breindahl T, Patients in medical treatment for attention deficit/hyperactivity disorder (ADHD): Are they at risk in drug screening? Attention deficit and hyperactivity disorders. 2018 Dec 7;     [PubMed PMID: 30536198]
[4] Mardomingo Sanz MJ,Sancho Mateo C,Soler López B, [Assessment of comorbidity and social anxiety in adolescents with attention deficit hyperactivity disorder: the SELFIE study]. Anales de pediatria (Barcelona, Spain : 2003). 2018 Nov 18;     [PubMed PMID: 30463795]
[5] Solmi M,Fornaro M,Toyoshima K,Carvalho AF,Köhler CA,Veronese N,Stubbs B,de Bartolomeis A,Correll CU, Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder. CNS spectrums. 2018 Nov 21;     [PubMed PMID: 30460884]
[6] Villas-Boas CB,Chierrito D,Fernandez-Llimos F,Tonin FS,Sanches ACC, Pharmacological treatment of attention-deficit hyperactivity disorder comorbid with an anxiety disorder: a systematic review. International clinical psychopharmacology. 2018 Nov 12;     [PubMed PMID: 30422834]
[7] Howes CF,Sharp C, Delusional infestation in the treatment of ADHD with atomoxetine. BMJ case reports. 2018 Sep 23;     [PubMed PMID: 30249731]
[8] Aldemir R,Demirci E,Bayram AK,Canpolat M,Ozmen S,Per H,Tokmakci M, Evaluation of Two Types of Drug Treatment with QEEG in Children with ADHD. Translational neuroscience. 2018;     [PubMed PMID: 30191077]
[9] Kobayashi H,Fujii K,Kobayashi M,Saito N,Okunushi K,Ebata R,Shiohama T,Sawada D,Shimojo N, Facial nerve palsy associated with atomoxetine-induced hypertension. Brain     [PubMed PMID: 30314873]
[10] Sharma A, Update on Common Psychiatric Medications for Children. Pediatric annals. 2018 Aug 1;     [PubMed PMID: 30102754]